In general, the present invention concerns microchip laboratory systems that carry out chemical and chemical-physical, physical, biochemical and/or biological processes, especially for analyzing or synthesizing substances on a substrate with a microfluid structure electrically, electronically, electromagnetically, mechanically or controlled in a similar manner. In particular, the invention concerns a device to operate such a laboratory microchip where a supply unit provides the potential necessary for moving the substance along the microfluid structure, and supply lines are provided to transmit the potential to the microchip.
The continuous development in this area is best illustrated by a comparison with corresponding developments in the field of microelectronics. In the field of chemical analysis as well, there is a substantial need (not least in the area of dinical diagnosis) to integrate existing stationary laboratory devices into portable systems and correspondingly miniaturize them. An overview of the most recent developments in this field of microchip technology is found in a collection of relevant professional publications published by Kluwer Academic Publishers (Holland, 1995) by A. van den Berg and P. Bergveld with the title, Micro Total Analysis Systems. The takeoff point for these developments was the established method of capillary electrophoresis; efforts had been made in the past to implement this method on a planar glass microstructure.
The basic required components for such a microchip system are shown in FIG. 1. They are basically divided into systems that have a material flow 1, and systems that represent an information flow 2 that occurs during an experiment. In the area of the material flow 1, means are necessary to supply 3 and transport 4 substances on the chip, and means are required to treat e.g. pretreat 5 the investigated substances. Furthermore, sensors 6 are required to detect the results of an experiment. The arising flow of information is essentially for controlling the transport of substance on the chip using e.g. control electronics 7. In addition, a flow of information occurs while processing in the signals 8 of the detected measured results, and especially while evaluating them 9.
Another motivation for miniaturization in the field of chemical analysis is to minimize the transport paths of the substances, especially between the substance supply and the respective detection point of a chemical reaction (see FIG. 2). In the fields of liquid chromatography and electrophoresis, it is understood that substances can be separated more quickly in such systems (test results are therefore available more quickly), and individual components can be separated with a higher resolution than is possible with conventional systems. In addition, the amount of substances (especially reagents) that micro-miniaturized laboratory systems use is greatly reduced, and the substance components are mixed much more efficiently.
The above-mentioned background is discussed in detail in an article by Andreas Manz et al. on page 5 ff. of the cited collection. The article also states that the authors have already manufactured a microchip consisting of a layer system of individual substrates that permits a three-dimensional transport of substances.
In contrast to creating a micro-laboratory system on a glass or plastic substrate, systems are mentioned in above-cited article that are based on a silicon-based microstructure. On this basis, apparently already-integrated enzyme reactors (e.g. for a glucose test), micro-reactors for immunoassays, and miniaturized reaction vessels for DNA quick assays have been created using the method of polymerase chain reaction.
A microchip laboratory system of the initially-cited type is also discussed in U.S. Pat. No. 5,858,195 where the relevant substances are moved by a system of connected channels integrated in a microchip. The movement of these substances in these channels can be precisely controlled using electrical fields that are applied along the transport channels. Given the highly-precise control of substance movement that this allows as well as the very precise dosing of the moved substances, the substances can be precisely mixed and separated, and/or chemical or physical-chemical reactions can be induced with the desired stochiometry. In this laboratory system, the integrated channels also have numerous substance reservoirs that contain the necessary substances for chemical analysis or synthesis. These substances are also moved out of the reservoirs along the transport channels by means of electrical differences in potential. The substances moved along the transport channels therefore contact different chemical or physical environments that allow the necessary chemical or chemical-physical reactions to take place between the respective substances. In particular, the prior-art substrate has one or more transport channel intersections at which these substances are mixed. By simultaneously using different electrical potentials at different substance reservoirs, the volumetric flows of the various substances through one or more intersections can be selectively controlled; a precise stochiometric template is therefore possible based just on the applied electrical potentials.
By means of the cited technology, complete chemical or biochemical experiments can be carried out using microchips tailored to the respective application. In handling microchips in measurement setups for experiments, the chips of the measuring system must be easily exchangeable, and the measuring setup must be easily adaptable to different microchip layouts. On the one hand, this adaptability is related to the respective arrangement of the substance reservoirs, the high voltage necessary for moving the substances on the chips, and the corresponding application of the voltage to the microchips. For such a measuring setup, you therefore need to run electrodes to the contact surfaces correspondingly provided on the microchip, and you need devices to supply the substances to the cited reservoirs. In particular, the microchips dimensions can only range from a few millimeters to approximately 1centimeter which makes the chips relatively difficult to handle.
A relevant arrangement for handling the microchip described at the onset is described in a prior publication, intentional patent application WO 9 8/05424. This has a base unit with a seat to receive an adapter that in turn receives a removable microchip. Corresponding counterelectrodes are provided on the adapter for the electrodes required to move the substances on the microchip. An electrical contact between the electrodes and the corresponding counterelectrodes is automatically created when the microchip is introduced into the adapter. Furthermore, the adapter itself contains devices that are required for evaluating the experimental measuring results such as a laser source and an associated photocell. In particular, the advantage of the adapter is that the base unit can work with numerous different microchips without having to adapt or even exchange the base unit. The disadvantage of this prior-art system is that the adapter is relatively involved since it e.g. contains the cited optical measuring devices. In particular, there are no devices in this arrangement for supplying the investigated substances and/or the reagents required for the experiment.
Moving substances by high voltage is, however only one variation among other conceivable solutions. For example, the difference in potential necessary to move the substances can also be created by applying a pressurized medium, preferably an inert gas, or another suitable gas medium or a liquid. Of course, when the microchip is subjected to a pressurized medium via a supply line, suitable seals must be supplied at the connecting site between the supply line and the microchip to prevent the pressurized medium from exiting at this connecting site. Alternatively, the movement of the substances can be generated by using a suitable temperature grid where the movement is brought about by thermally dilating or compressing the respective substance.
In particular, the selection of the respective medium to provide potential or force to move the substances on the microchip depends on the physical properties of the substances themselves. With substances that have charged particles, for example charged or ionized molecules or ions, the substances are preferably moved using electrical or electromagnetic fields of suitable strength. The paths traveled by these substances depend in particular on the field strength and how long the field is applied. In contrast, substances that do not have an electrical charge are preferably moved using a flow medium such as an inert gas. Given the very small dimensions of the transport channels in the microchip, only a relatively small volume of air is required on the level of picoliters. For substances that have a relatively large thermal expansion coefficient, a thermal procedure may be recommendable to move them, yet only when the resulting increase in temperature does not influence the kinetics of the reaction during the experiment.
Given the potential complexity of the reactions, the number of required contact electrodes can be several hundred or even more. In addition, these substances can be moved in transport channels with any three-dimensional design, e.g., in troughs or grooves, or hollow channels that are enclosed on all sides. Hollow channels can be filled with a liquid or gelatinous buffer medium to further control or set the precise flow rates of these substances. The flow rates can be precisely set by the applied electrical fields based on the movement of charged particles through such a gel. In addition, it is possible to place to the required reagents or even the investigated substances on the microchip beforehand.
By using a buffer gel or buffer solution, mixtures of charged molecules can be advantageously moved through the medium by an electrical field. Several electrical fields can be applied simultaneously or sequentially to separate substances or correspondingly supply the respective substances on a precise schedule, possibly with different time gradients. This procedure can be used to create complex field distributions or fields that migrate beyond the separating medium. Charged molecules that travel through gels with a greater degree of mobility than other substances can thereby be separated from slower substances with less mobility. The precise spatial and temporal distribution of the fields can be determined by corresponding control or computer programs.
In addition, micromechanical or micro-electricomechanical sensors are presently being considered for use in the cited area of microfluid engineering, e.g. micromechanical valves, motors or pumps. A corresponding perspective on possible future technologies in this field is provided by a relevant article by Caliper Technologies Corporation that can be retrieved on the Internet at xe2x80x9cwww.Calipertech.comxe2x80x9d.
When this new technology becomes accepted by the affected circle of users, the cited microchips will quickly become a mass-produced article and catch on similar to immunoassays as a quick test in the fields of laboratory diagnostics and clinical diagnostics. There is therefore a substantial need for a measuring setup for the practical handling and operating of such a microchip that simplifies manipulation of the chips so that they can be used in the cited laboratory environment quickly and easily in the fields of chemistry, biology or medicine by lab assistants who generally have a relatively low amount of technical skill.
This would also allow corresponding large-scale acceptance of the chips and relatively easy and quick evaluation of the measuring results. In addition to the appropriate and easy manipulation of the chips, users should have to deal as little as possible with the cited supply devices (especially for any required high voltage) or any other necessary technical devices.
With the discussed systems, the connecting elements between the supply lines of the supply devices and corresponding means of conveyance on the microchip are in particular subject to more-or-less strong mechanical, electrical or chemical wear or corrosion, and are often strongly soiled when they directly contact the substances on the microchip. Of particular significance is that the utilized substances (especially the reagents) in many of the relevant chemical experiments require an extremely high degree of purity. The slightest amount of impurities in the supply lines can substantially falsify the measurement results. In addition, a generic device should be easily and quickly convertible for measurements using microchips with different layouts.
The cited problems are solved with a device according to the invention for operating or manipulating a cited laboratory microchip by providing a releasable interface element between the supply unit and the microchip to bridge or provide a conductive connection to the supply lines with the microfluid structure. The suggested interface element hence primarily allows the supply devices to be easily adapted to microchips with different layouts. In addition, only the interface element directly contacts the microchip and can become soiled or worn. The interface elements can therefore be advantageously exchanged with new elements between individual experiments to reduce to a minimum the danger of contamination by substances on the microchip.
The suggested interface element preferably has electrodes or supply channels for supplying the microchip with electrical, mechanical or thermal energy by means of which the necessary potential can be generated for the microfluid movement of the substances on the microchip. If the substances on the microchip are moved by means of a pressurized medium such as an inert gas, a similar gas medium or a liquid, supply channels are provided in the interface element to supply the microchip with this pressurized medium.
In an altered embodiment where additional supply means are provided to supply the microchip with at least some of the necessary substances for processing (especially analyzing or synthesizing), the interface element has corresponding supply channels to supply the microchip with these substances.
Of course corresponding seals need to be provided here as well to prevent the liquids or gases from exiting, especially when they are under pressure.
The interface element according to the invention can also be formed by a substrate especially consisting of a ceramic or polymer material in which the cited electrodes or supply channels are embedded. With these materials, the interface element can be highly resistant to the utilized chemical substances, and they can also be easily cleaned with chemicals and then reused.
In an advantageous development of the inventive idea, the interface element can be affixed to the supply means by a bayonet block. Such an attachment allows the interface element to be easily and quickly exchanged, e.g., after each experiment.
In addition, a first coding means can be on the interface element for identification that interacts with a corresponding second coding means on the supply means. This measure makes the device according to the invention particularly safe to use since it effectively prevents interface elements that are incompatible with the supply from being accidentally used or installed.
In addition, the microchip can be in a first assembly, and the supply means as well as the interface element can be in a module releasably connected to a second assembly. The module is preferably designed as an insertable cassette or cartridge. The entire device can be designed to be set up as a stationary unit or a portable device for ambulatory local experiments, e.g., for a patient. In a first embodiment, the suggested module has the cited first supply means. The substances required for the respective experiment are either supplied along separate paths to the microchip or via a second supply unit that also can preferably be in the suggested module.
To further increase operational reliability, a magnetic/Hall sensor can be provided to identify or recognize the second assembly or determine the presence of a module (cartridge) in the second assembly, and a shut-off device or warning device that works with the sensor can also be provided.